Dr. Darrin Lew

catalyst

endo:exo

8 ee%

Mg(II)-6 • ClO4

93:7

72 (S)

Mg(II)-6 • ClO4 + 2H2O

95:5

73 (R)

Cu(II)-6 • OTf

95:5

30 (S)

Zn(II)-6 • SbF6

98:2

92 (R)

Cu(II)-7* OTf

97:3

98 (S)

Zn(II)-7 • SbF6

95:5

38 (R)

n

2+

/Mi R R

2X- J

R = Ph, (S,S )-6 R = f-Bu, (S,S )-7

Tetrahedral

Ri O^ff H2O

ri^SEM^O-O

Octahedral in plane

Scheme 2.2 Reversal of stereoselectivity in the oxazoline-promoted Diels-Alder reaction

opened the way to the development and catalytic application of different classes of monodentate phosphorous derivatives [43-46], previously ignored on the basis of the assumption that a bidentate coordination fashion was essential to ensure conformational rigidity of the catalyst as a key feature for effective chiral induction (Scheme 2.4). The great potential of monodentate ligands, whose synthesis is more straightforward and economical than that of their bidentate counterparts, is still far from being fully explored and progress in this field is highly expected.

Mechanistic studies for many reactions have also highlighted that intermediates in catalytic cycles are in most cases nonsymmetrical and in such occurrences the use of sterically and electronically divergent coordinating groups should permit more effective enantiocontrol than C2-symmetric ligands. In this context, phos-phineoxazolines (PHOX) have been developed by Pfaltz [47] as mixed P,N-bidentate ligands and the distinct features of a p-acceptor P-group and a r-donor N-group have been successfully exploited, among different reactions, in Pd-cata-lyzed allylic substitution. Indeed upon substrate complexation, the two allylic termini were differentiated by a combination of steric and electronic effects and the nucleophile preference in attacking the allylic carbon trans to the phosphino group resulted in excellent selectivity and up to 99% enantiomeric excesses (Scheme 2.5). A variety of mixed ligands containing an oxazoline ring in

O , n o^M v(°)"9 (°-1% mol> OSiMea y + Me3S|CN —- T

Ph^H CH2Cl2, rt Ph^CN

O , n o^M v(°)"9 (°-1% mol> OSiMea y + Me3S|CN —- T

Ph^H CH2Cl2, rt Ph^CN

° Ti(IV)-9 • Cl2 (1°% mol) \_/ BU4NF, THF ^ \_/

Scheme 2.3 Beyond alkene epoxidation: versatility of salen ligands conjunction with additional P-, N-, O- or S- coordinating atoms and different chiral elements, as stereogenic carbon(s), axis or plane, are today available and widely employed in asymmetric synthesis [48].

In the same way, dialkylzinc addition to aldehydes has gained selectivity in many instances by using N,O- heterobidentate ligands and chiral aminoalcohols have became very popular catalysts for this reaction [49-51]. In a comparative study on the performances of C2- versus Ci-symmetrical catalysts the latter were found more effective in several reactions [52] and the development of new ligands with less usual combinations of coordinating atoms, such as the P,S-, P,O- and N,S-variety, is a promising way to expand the molecular diversity of asymmetric catalysts. Mixed phosphine-phosphinites and phosphine-phosphites are other

10 X = NR1R2 phosphoramidites 13 X = OR phosphinites

11 X = OR phosphites 14 X = NR1R2 aminophosphinites

12 X = Me, Et, Ph phosphonites 15 X = R phosphepines

P-Ph

16 R = Me, Ph phospholanes

-PPh2

J^PPh2

PR1R2

18 R = H, Et, OMe, OBn 19 R = Me, Ph 20 R = H, OMe Scheme 2.4 C2-symmetric (a) and Ci-symmetric (b) monodentate phosphorous ligands

PHOX

-CH(COOMe)2

PHOX

" HPd

-CH(COOMe)2

-CH(COOMe)2

Scheme 2.5 Pd-promoted allylic alkylation with phosphinooxazoline ligands

Fig. 2.3 Strategies toward more sustainable catalysts

Non-enantiopure ligands

Metal- free catalysts

Structural optimization of ligands

Alternative metals

Non-enantiopure ligands

Metal- free catalysts

Structural optimization of ligands

Alternative metals

interesting examples of bidentate non-symmetrical ligands, characterized by two phosphorous atoms with different p-acceptor properties, that have shown comparable and in some cases superior activity with respect to the milestone ligands in Rh-mediated hydrogenation and hydroformylation reactions [53].

Although several transition-metal based catalysts are nowadays routinely used in the preparation of chiral fine chemicals, further improvements in a "green" direction are possible in order to overcome the drawbacks related with the generation of metal residues and organic solvent wastes, the use of special equipments to ensure dry and inert reaction conditions, the costs connected with some precious metals and the synthesis of enantiopure ligands.

In this context, the availability of even more active and selective ligands can allow lower catalyst loading and simplification in the purification steps for the products with direct consequences on waste reduction. Other promising approaches concern the use of alternative metals or non enantiopure ligands whereas organocatalysis has emerged as a powerful strategy in metal-free asymmetric synthesis (Fig. 2.3).

Since subtle variations in the ligand structure can sensibly affect the asymmetric induction by modifying the chiral environment around the metal, the identification of the suitable catalyst for a given transformation still poses one of the most challenging endeavour in the development of effective processes and it is often the result of knowledge based intuition or serendipity as well as of time-consuming trial and errors optimization of other concurrent factors (metal, solvent, additives etc.). In the traditional iterative approach, based on the synthesis of one catalyst at a time and evaluation of its performances, ligands accessible through modular synthesis are preferred since structural modifications can be easily tailored by joining small units together through high yielding reactions. As some examples, the diversity of ring substituents in bis-oxazolines and phosphinoox-azolines comes from readily available chiral aminoalcohols whereas libraries of Schiff-bases can be obtained by systematic variation of both the aminic and aldehydic moieties. Structural modifications on carbon backbone or phosphorous atom of phospholanes can be easily introduced through a two step synthesis in which chiral 1,4-diols are converted into the corresponding cyclic sulphates and then treated with primary phosphines (Scheme 2.6).

A) Bu2SnC!2, xylene; B) MeSO3H, CH2C!2, MS; C) Ph3P/CCl4/Et3N; D) ZnCl2, C!CH2CH2C!

i) BuLi, Et2O, ^S HO NH2 0 ZnC2 PhC -78 °C II I ■ \ / 2 reflux

NC" ^f N) pr1r2c! NC" ^f ) C ii) bpy Br pR1R2 R3 R4 CHCl3, rt

i) SOCl2

ii) NaIO4, RuCl3

base

Scheme 2.6 Examples of modular ligands

+ PH2R1

In an alternative strategy, combinatorial methods have been applied to enan-tioselective catalysis as a powerful tool for the generation and simultaneous test of a considerably larger number of candidates, leading to enhanced chances to find the catalyst with higher performances and the best reaction conditions [54]. It has been also underlined that large structure-selectivity databases from combinatorial approach can be particularly useful to optimize novel and unexplored reactions and to promote the related mechanistic studies.

Some libraries of modular catalyst have been prepared by automated solidphase synthesis technology [55] and, despite of the enormous number of accessible compounds in a "split-and-pool" method, the parallel approach has been preferentially used since it does not require deconvolution and the composition of each vessel is easily defined by its position in a multi-well array. To the synthesized ligands, usually tested in their resin-bound form for preliminary screenings and in solution after cleavage for subsequent refinement, the reagents are added and the reaction course monitored by using a suitable high-throughput system capable of assaying activity and/or enantioselectivity in reasonable time. The search for reliable access to these data has stimulated the development of different detection systems[56-59] among which circular dichroism detection applied to HPLC on non-chiral stationary phases [60] and capillary electrophoresis on parallel columns containing a chiral selector as electrolyte coupled with laser-induced fluorescence or DAD detection [61, 62] have been reported as super-high-throughput analytical tools for simultaneous determination of yields and enantiomeric excesses of the products.

homocombinations heterocombination

COOMe ^^COOMe

Ligands

Rh(COD)2BF4 L1/L2

COOMe J^COOMe

(R) Ligands

Scheme 2.7 Catalytic activity of mixtures of monodentate ligands

More recently, the application of supramolecular principles to catalysis [63] has promoted the development of dynamic combinatorial libraries as collections of transient compounds reversibly assemblied under thermodynamic control from a number of building blocks [64, 65]. For given experimental conditions, the library composition is biased toward those members that form the most stable assemblies or aggregates. One of the most appealing application of this strategy makes use of a mixture of monodentate ligands, in place of a bidentate one, and their self-assembly in all the possible combinations around the metal allow to expand the size of library and catalyst diversity without the need to really synthesize new ligands. Indeed, for n monodentate ligands not only n homocombinations [M-LxLx] or [M-LyLy] are possible but also n(n-1)/2 heterocombinations [M-LxLy] and even mixtures of chiral ligands with achiral ones can be effective in their heterocombinations [66]. Enhanced enantioselectivities for heterocombina-tions of two monodentate ligands with respect to the corresponding homo-complexes have been observed in Rh-catalyzed hydrogenation of different olefins with monophosphonites or monophosphites [67-69] (Scheme 2.7) as well as in conjugate addition of aryl boronic acids to enones or nitrostyrenes with Rh-phosp-oramidite complexes [70].

In an alternative approach, the emulation of a catalytically active chelate complex between a metal and a bidentate ligand has been achieved by using monodentate ligands bearing substituents with complementary binding sites that mutually interact through a range of non covalent interactions (van der Waals, p-stacking and dipole-dipole interactions, hydrogen bonding) [71, 72]. Some monophosphites covalently bound to urea derivatives and mixtures of phospho-nites containing aminopyridine or isoquinolone moieties have been reported as interesting examples of supramolecular catalysts in which two molecules of ligands, held together by means of multiple hydrogen bonds, behave as a bidentate

bidentate ligand

MeO2C O

Rh(COD)2BF4 L1/L2

CH2Cl2, H2, rt Ligand

MeO2C O

Meifl^N Me H

100%

(S)-11a/(S)-11a (S)-12d/(S)-12d (S)-12e/(S)-12e (S)-12d/(S)-12e

98 94

(S)-11a/(S)-11a (S)-12d/(S)-12d (S)-12e/(S)-12e (S)-12d/(S)-12e

98 94

Scheme 2.8 Emulation of a bidentate ligand by supramolecular assembly of monodentate ligands

ligand in creating a chiral environment around rhodium in asymmetric olefin hydrogenation (Scheme 2.8) [73, 74].

In the optimization of catalysts for asymmetric synthesis, some studies has been focused toward the use of more environmentally benign metals [75], since it is well-known that the majority of ''heavy metals'' display bioaccumulation and toxic effects on many living systems [76], despite of some of them (iron, copper, manganese and zinc) are essential for human health at suitable doses. However, classification of ''light'' beryllium as a human carcinogen [77] gives clear evidence that biological toxicity of metals results from different factors other than the atomic mass and correlation scales with ''softness'' of metal ions, charge and K values for their binding to soft ligands have been proposed [78-80].

Among the metals more recently taken into consideration, iron is economical and relatively nontoxic and iron-complexes have displayed valuable potential as catalysts for reduction, oxidation and coupling reactions [81-83]. Some achiral iron catalysts mimicking the active site of non-heme iron enzymes as the Rieske dioxygenase have been shown able to catalyze cis-dihydroxylation of olefins with H2O2 [84, 85] and the development of the asymmetric version of such process could represent a promising benign alternative to the osmium-based Sharpless'

O OH

Scheme 2.9 Iron-promoted asymmetric cis-dixydroxylation of olefins dihydroxylation. However, asymmetric iron-promoted reactions have been mainly restricted to transfer hydrogenation of ketones [86, 87] and a single example of cis-hydroxylation of olefin was reported with complex 22 (Scheme 2.9) to give the corresponding diols in high ee (up to 97%) but rather unsatisfactory yields [88].

Indium and scandium have been also evaluated as useful metals for their low toxicity and high stability to air and moisture, the latter feature offering the possibility to recover and recycle the catalysts and perform reactions in water-based solvents. The moderate Lewis acidity and low heterophilicity of these metals make their complexes effective catalysts for C-C bond-formation reactions with good tolerance of different functional groups.

The asymmetric carbonyl-ene, an important reaction for the atom-economic synthesis of homoallylic alcohols, has been carried out with "pybox" complexes of scandium or indium [89, 90] and a significant counterion effect on the reaction rate and selectivity was evidenced [91] (Scheme 2.10). Other interesting applications in enantioselective allylation of ketones [92, 93], Mannich-type reaction of aldimines [94] and asymmetric ring opening of meso epoxides [95] have been reported using N,N'-dioxide chiral ligands.

Enantioselective catalysis with gold(I) is still in its infancy but future developments could be expected due to the peculiar features of this metal that behaves as a high electrophilic but relatively non-oxophilic Lewis acid and displays stability to air oxidation, good chemoselectivity and good functional group compatibility. Complexes of gold(I) with phosphines have been mainly used in the activation of alkynes and allenes toward nucleophilic addition [96, 97] and some asymmetric intramolecular hydroarylation [98], hydroalk-oxylation [99] and hydroamination [100] reactions leading to carbocyclic and heterocyclic compounds have been developed by Widenhoefer's and Toste's groups (Scheme 2.11). A pronounced counterion effect was evidenced in some cases and the use of a 1:1 mixture of an achiral gold complex and phosphoric acid (R)-26 as sole source of chirality was sufficient to achieve excellent

R OH

R OH

R = H, R1 = Et, R2 = H 98%, 95% ee R = CF3, R1 = Me, R2 = H 99%, 95% ee R = H, R1 = Et, R2 = OMe 97%, 96% ee R = CF3, R1 = Me, R2 = OMe 99%, 95% ee

"Ph

Scheme 2.10 Indium- and scandium-catalyzed carbonyl-ene reactions

X = OTs,ClO4 R = O 67%, 93% ee R = NCbz 97%, 81% ee

"X^Ar

[Au2(R)-25]Cl2 (3% mol) AgBF4 (6% mol) R. toluene, -40 °C

X = OTs,ClO4 R = O 67%, 93% ee R = NCbz 97%, 81% ee

R = H, R1 = OMe (S)-24 R-R1 = -OCH2O- (S)-25

NHSO2Mes

NHSO2Mes

MesSO2

Scheme 2.11 Gold(I) activation of allenes asymmetric induction in the hydroamination of allene 27 to afford the cyclic product in 88% yield and 98% ee [101].

Although in catalytic asymmetric synthesis a 100% optical purity of the catalyst is assumed as a condition to gain the maximum enantioselectivity, the use of non-enantiopure chiral sources increases the sustainability of a catalytic process in

(±)-Cat-► (RR)-dimer + (SS)-dimer + 2 (RS)-dimer

R-product S-product more stable and/or less active more stable and/or less active

linear relationship

%ee catalyst linear relationship

%ee catalyst

Scheme 2.12 Asymmetric amplification of chirality terms of ''chirality economy'', defined as the ratio (ee% x yield % of product)/ (ee % x mol% of catalyst), other than the obvious advantages in the efforts required for the synthesis and/or resolution of chiral ligands. Different effects leading to a non linear relationship between the optical purities of the catalyst and the product have been mechanistically investigated and high levels of enantioselectivity have been reported for some catalytic systems based on non-enantiopure or racemic ligands.

Asymmetric amplification effects observed with some scalemic ligands have been rationalised with the formation of heterochiral (RS) or homochiral (RR or SS) dimeric species of the catalyst and two models, differing in the nature of the active catalyst, have been proposed by Kagan [102] and Noyori [103]. In both models the formation of a less active heterochiral (RS) dimer results in the subtraction of the minor enantiomer of the ligand from the catalytic system, so that the reaction can be stereocontrolled by the more active homochiral dimer (RR or SS), in this form or in equilibrium with its monomers (Scheme 2.12). Since the amount of available catalyst in the reaction system is siphoned off by the formation of less active aggregates, the asymmetric amplification comes at expense of reaction rate and kinetic studies have been proved useful diagnostic tools for mechanistic insight and identification of active catalytic species [104].

Strongly positive deviations from linearity, resulting in optical purity of the products higher than that of catalysts, have been observed in nucleophilic addition of dialkylzinc to carbonyls (Scheme 2.13), 1,4-addition of organozinc or organocuprates to enones and titanium-catalysed epoxidation, sulfoxidation, Diels-Alder and carbonyl-ene reactions [105].

In chiral poisoning approach [106], a rather inexpensive chiral additive deactivates one enantiomer of the catalyst by selective complexation, so leaving the other enantiomer in more enantioenriched form available for catalysis and in an ideal case the addition of one-half an equivalent of poison to a racemic catalyst would leave one-half of an equivalent of active homochiral catalyst, with a process assimilable to a in situ resolution. In any case, the level of asymmetric induction can not exceed the level obtained with the enantiopure catalyst.

The feasibility of this approach was impressively demonstrated in the hydrogenation of methyl-3-oxobutanoate with Ru-complex of racemic diphosphine (±)-28 in the presence of diamine (S)-29 that gave the (R)-product in 99.3% ee, a value perfectly comparable with 99.9% ee obtained with (R)-28/Ru-catalyst, in

Et2Zn, toluene

Et2Zn, toluene

Scheme 2.13 Positive asymmetric amplification in dialkylzinc addition to aldehydes

consequence of quantitative formation of deactivated RuCl2[(S)-28/(S)-29] [107] (Scheme 2.14). The addition of catalytically inactive (-)-DIPT-Ti(O-i-Pr)4 to (±)-BINOL-Ti(O-i-Pr)4 led to a moderately efficient poisoning system for chloral-ene reaction [108] whereas better enantioselectivities were achieved in the addition of allyltributyltin to aldehydes [109], in both cases as result of the deactivation of (R)-BINOL enantiomer.

In the conceptually opposite strategy of asymmetric activation the addition of a chiral modifier to a racemic catalyst generates two diastereoisomeric complexes with matched and mismatched chiralities, one of which is more active and enantioselective than the original catalyst, so that the product ee is dependent on their relative concentrations, turnover frequencies and enantioselectivities [110]. This approach, effectively applied by Noyori in asymmetric hydrogenation of ketones with racemic Ru-BINAP catalyst in the presence of enantiopure (S,S)-DPEN [111], has found advanced application in the activation of atropiso-merically flexible (tropos) ligands whose axial chirality can be fixed upon dynamically controlled complexation with a metal under the influence of a chiral additive [112]. In such way, achiral pro-atropisomeric ligands can be used instead of chirally rigid racemic ones, that lead to the formation of competitive complexes from each enantiomer.

As an example, the treatment of BIPHEP-Pd(SbF6)2 30 with 1 eqv of (R)-2,20-diamino-1,1'-binaphtalene (DANB) gave an initial 1:1 diastereoisomeric mixture that by heating at 80 °C underwent complete tropoinversion to the more stable

Scheme 2.14 Chiral poisoning approach

complex (R)-BIPHEP-(R)-DANB 31, structurally characterised by X-ray analysis, able to act as an enantiopure catalyst in asymmetric hetero Diels-Alder reaction of ethylglyoxylate and 1,3-cyclohexadiene [113] (Scheme 2.15). Following the same approach, BIPHEP-Rh and 2,20-biphenol-Ti complexes were activated with (S)-20-amino-1,10-binapht-2-ol [114] and cinchonine [115], respectively, to give highly entioselective catalysts for ene-type cyclization of 1,6-enynes and Strecker reaction of N-tosylimines.

2.3 Metal-Free Catalysts

The first examples of enantioselective intramolecular aldol cyclizations catalyzed by (S)-proline 32 without the participation of any metal were independently reported by Hajosh and Parrich [116] and Eder et al. [117] (Scheme 2.16a) in early 70s but the potential of this catalytic reaction was not fully realised by the scientific community until 2000 when List described the first direct intermolecular aldol condensation between different aldehydes and acetone promoted by 30% mol of the same aminoacid (Scheme 2.16b) [118]. High excess of acetone was required to suppress the reaction of aldehydes with the catalyst and aldols were obtained with optical purities ranging from 60% up to 96% ee with isobutyraldehyde. Since aldol condensation under classical Lewis acid catalysis required manipulation of substrates, converted into more reactive derivatives as silyl enol ethers, this report provided an atom economically breakthrough in this C-C bond forming reaction.

The proposed mechanism, clearly resembling the action mode of class I aldolase and successively supported by experimental [119] and computational

Scheme 2.15 Catalyst activation of a tropos ligand

[120] data, involves the activation of ketone through an enamine intermediate followed by its reaction with an electrophile component assisted by the adjacent carboxylic group in an ordered transition state (Scheme 2.16c).

In the same year MacMillan reported the enantioselective Diels-Alder condensation of enals with different dienes in the presence of chiral imidazolinone 33 as catalyst and the activation of substrates through a catalyst-substrate iminium intermediate was envisioned as a useful alternative to classical Lewis acid

T""H

enamine w

OH O

RCHO

OH HO

RCHO

Scheme 2.16 Organocatalytic intra- and inter-molecular aldol reactions (a-b) and proposed mechanism (c)

catalysis [121]. The origin of stereocontrol resides in the selective formation of (E)-iminium isomer, driven by sterical hindrance of the geminal methyl substit-uents, and in the shielding of the re-face of olefinic bond by benzyl group of 33 that leaves the si-face of substrate exposed to cycloaddition (Scheme 2.17).

After these two pioneering researches an explosion of papers appeared in the literature witnessing the interest of organic chemists toward ''organocatalysis'', a term coined to indicate catalysis promoted by low molecular weight organic molecules, that has then emerged as a powerful strategy complementary to metalbased asymmetric catalysis. Organocatalysts meet several criteria established in green chemistry since they are non-toxic, stable to air and moisture with consequent operational simplicity and, in many cases, are available from natural sources or easy to prepare at relatively low cost. Beside proline other classes of effective organocatalysts have been discovered and most of them can be classified on the basis of their Lewis acid/base and Bronsted acid/base character [122] or in function of the activation modes [123], strictly related to the nature of intermediates generated from catalyst interaction with the substrate fuctional groups (carbonyl, alkene or imine) in a highly organized and predictable manner.

CHO R

90%ee (endo) 86% ee (exo) R = Ph, n = 1 99%, exo :endo 1.3:1,

93% ee (endo), 93% ee (exo) R = H, n = 2 82%, exo :endo 1:14, 94% ee (endo)

Scheme 2.17 Organocatalytic Diels-Alder through iminium intermediate

Enamine-based oganocatalysis with proline and diamines has been extended to different aldol, Michael or Mannich reactions [124] whereas a,a-diarylprolinol silyl ether 34 showed to be an excellent catalyst with general applicability in asymmetric direct a-functionalisation of carbonyl compounds [125]. Among the most notable examples, proline-catalyzed aldol reaction of hydroxyketones to afford anti-diols [126] revealed to be an effective protocol complementary to Sharpless dihydroxylation while a-fluorination of aldehydes in the presence of 34 offered a general procedure for the introduction of C-F bonds (Scheme 2.18a-b). Interestingly, the reversal of the syn-diastereoselectivity observed in proline-cat-alyzed Mannich reaction of aldehydes and protected a-iminoglyoxylate was achieved through a computer-aided rational design of catalyst 35 [127]. It allowed better stabilization of the syn-enamine intermediate evolving toward the anti-Mannich products thanks to the sterical contribution of C-5 methyl substituent and the larger distance between amino and C-3 carboxylic groups (Scheme 2.18c-d).

In iminium catalysis, the higher reactivity of iminium ion compared to carbonyl species activates a,b-unsaturated aldehydes and ketones to 1,4-addition of several nucleophiles and cycloadditions [128]. The enantioselective addition of malonates to enones and enals has been screened with different organocatalysts and valuable application in the formal syntheses of (—)-paroxetine and (+)-femetoxine was reported by J0rgenson's group [129]. Imidazolinone 36 gave high asymmetric induction in the addition of electron-rich benzenes and heteroaromatic nucleo-philes to enals [130] (Scheme 2.19) and useful intermediates for the synthesis of biologically active compounds, as homotryptamines, (+)-curcuphenol and rhazinilam-related alkaloids, have been prepared by this route.

More recently the iminium-activation platform has been extended to hetero-atom-containinig nucleophiles and prolinol 34 displayed versatility in promoting